SK40494A3 - Method for preparing benzo/b/naphthyridines - Google Patents

Abstract

Method for the preparation of benzo[b]naphthyridines having the general formula (I) wherein the meaning of the substituents is stated in disclosure and consists in that 1) an amine having the general formula R'-NH-CH2-CH2-R'' is condensed, wherein R'' is alkyloxycarbonyl, cyano, carbamyl, alkylcarbamyl, benzylcarbamyl, hydroxyethylcarbamyle, dialkylaminoethylcarbamyl or dialkylcarbamyl whose alkyl parts may optionally form, with the nitrogen atom to which they are attached, a heterocycle with 5 or 6 members containing optionally another heteroatom selected amongst oxygen, sulphur or nitrogen and optionally substituted on the nitrogen by an alkyl radical, on a chloro fluoro quinoline having the general formula (II) wherein R1 is an alkyl radical, the alkyl radicals mentioned hereabove having from 1 to 4C and being straight or branched; 2) a cyclisation of the fluoroquinoline of general formula (III) is effected, wherein R1 is defined as hereabove in 1); 3) an oxidation of tetrahydro-1,2,3,4 benzo[b]naphthyridine-1,8 having a general formula (V) is effected, and optionally, the ester obtained is transformed into an acid and optionally into a salt. Disclosed are also new benzo[b]naphthyridines prepared by this method.

Description

Process for preparing benzo (b) naphthyridines

Technical field

The invention relates to a process for the preparation of benzo (b) naphthyridines.

BACKGROUND OF THE INVENTION

The benzo (b) naphthyridines of the formula I as well as their preparation and use for the preparation of antibacterial agents are described in U.S. Patents 4,970,213 and 4,990,515.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of the benzo (b) naphthyridines of formula (I)

wherein R is carboxyl, alkoxycarbonyl, cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl, the alkyl moieties of which may optionally form with or on a nitrogen atom, A 6-membered heterocyclic group, optionally containing a further heteroatom

A is selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted on the nitrogen by alkyl, R 'is hydrogen, alkyl, fluoroalkyl, carboxyalkyl, cycloalkyl of 3 to 6 carbon atoms, fluorophenyl, difluorophenyl a Hal, a halogen atom, and salts thereof, if any.

It has now been found that benzo (b) naphthyridine derivatives of formula I can be prepared from a quinoline derivative of formula II

Hal

(II) wherein Hal is as defined above and R 1 represents a hydrogen atom or an alkyl group by carrying out the following reaction steps:

1) condensation of an amine of formula III

R'-NH-CH2-CH2-R8 wherein R 'is as defined above and R is alkyloxycarbonyl, cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl moiety, may optionally form, with the nitrogen atom to which they are attached, a 5- or 5-membered heterocyclic group, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted on the nitrogen by an alkyl group, with a chlorofluoroquinoline of general formula of formula II wherein R 1 is an alkyl group,

2) cyclization of the fluoroquinoline of formula IV thus obtained

r 'wherein R', R and Hal are as defined above and R 1 is as defined in 1) above, and

3) oxidation of 1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine of formula V

wherein Hal, R 'and R optionally convert the I into the acid in which R is obtained as defined above, and then the ester of the formula represented by a carboxyl group, and the acid to the salt.

The novel process of the invention is of particular interest in that it allows to obtain improved yields, as well as the fact that it is no longer necessary to prepare the above derivatives using unstable intermediates.

In the formulas above or below, the alkyl groups have a straight or branched carbon chain of 1 to 4 carbon atoms. Otherwise, Hal is preferably chlorine or fluorine.

The condensation of the beta-amino ester of formula III is carried out using a quinoline of the novel derivative of formula II, the carboxyl function of which is optionally protected in the form of an ester group. It is operated in an alkaline medium in an organic solvent such as an aromatic hydrocarbon (e.g. toluene), amide (dimethylformamide, N-methylpyrrolidone), ether (e.g. tetrahydrofuran), sulfoxide (e.g. dimethylsulfoxide), chlorinated solvent (dichloromethane, dichloroethane or chlorobenzene) or alcohol , at a temperature of -10 to 120 ° C.

Examples of useful bases include alkali metal carbonates (sodium carbonate or potassium carbonate), alkali metal alkoxides or alkali metal hydrides (sodium hydride).

Of course, in the alternative case where R 'is a carboxyalkyl group, it may be pre-protected prior to the reaction itself. The cleavage of the protecting group is preferably carried out only after oxidation 3). The introduction and cleavage of the protecting group is carried out by conventional methods which do not adversely affect the rest of the molecule, in particular by the following methods.

The cyclization reaction of the product of formula (IV) is carried out under basic conditions. Preferably, it is operated at a temperature between -70 to 120 ° C, particularly preferably at -30 to 120 ° C, in the presence of a base such as an alkoxide (e.g. sodium ethoxide, sodium methoxide, potassium tert-butoxide), an alkali metal hydride (e.g. sodium hydride) or also an alkali metal hydroxide if a phase transfer mechanism is chosen. Preferably, the reaction is carried out in an aprotic polar solvent (e.g. dimethylformamide or tetrahydrofuran) or an alcohol (e.g. ethanol or methanol), glyme or glycol (e.g. ethylene glycol). When the reaction is carried out by a phase transfer mechanism, it is preferably operated in a chlorinated solvent such as methylene chloride, the base being in solution in the aqueous phase.

The oxidation is carried out with hydrogen peroxide, optionally in the presence of potassium iodide, in an organic solvent such as an alcohol (e.g. ethanol) at a temperature between 0 and 120 ° C. It is also possible to work in a biphasic medium in a mixture of water and a chlorinated solvent (dichloromethane, dichloroethane).

The quinoline derivative of formula (II) may be obtained by the method described in U.S. Pat. No. 4,970,213 and optionally subsequent esterification of the product obtained by conventional methods.

The quinoline derivative of the formula II can also be obtained by chlorination of the quinoline derivative of the formula VI

H wherein R 1 and Hal are as defined above

Said chlorination is carried out using known chlorinating agents which do not undesirably interfere with, in particular, phosphorus pentachloride at the temperature of the intermediate part of the molecule. It acts with sulfuryl chloride or chloride between 0 and 150 ° C. Of course, when starting from a quinoline of formula VI in which R 1 is a hydrogen atom, it is necessary to pre-protect the carboxyl function.

If it is desired to obtain an acid of formula (II) in which R 1 is hydrogen, hydrolysis of the ester obtained is carried out by any known method which does not adversely affect the rest of the molecule. The introduction and deprotection of the carboxyl function may be accomplished using any suitable protecting group and any suitable compatible method. The introduction and cleavage of the protecting group should not adversely affect the rest of the molecule. In particular, the methods described by T. W. Green in Protective Groups in Organic Synthesis, by A. Wiley Interscience Publication (1981) or by Mc.Omie in Protective Groups in Organic Chemistry, Plenum Press (1973) are used.

The quinoline derivative of formula VI can be prepared by acidic cyclization of the nitro derivative of formula VII

wherein Hal is as defined above, R '1 is as R 1 except for hydrogen, and Ra is as R' x or is carbamoyl, sulfonyl or cyano, and optionally subsequent release the carboxyl function when it is desired to obtain ^a derivative in which Rx represents a hydrogen atom.

; The acidic reaction is carried out in the presence of iron at a temperature between 0 and 130 ° C using any organic or non-non-acid which does not adversely affect the remainder of the molecule. By way of example, acetic acid or formic acid may be used, and the reaction may also be carried out using dilute hydrochloric acid or dilute sulfuric acid in an aqueous-alcoholic medium. It will be appreciated that this acid will be selected depending on the desired product. If it is desired to obtain an acid of formula (VI), it is preferred to use a stronger acid under conditions where the ester is hydrolyzed simultaneously. It is also preferred to start from the product of formula (VII) wherein R @ 1 is cyano. Of course, in cases where an ester has been obtained and it is desired to obtain an acid of formula VI in which R 1 is hydrogen, the ester hydrolysis can also be carried out after the cyclization reaction by any known method to recover the acid from the ester. undesirable interference with the rest of the molecule.

The ester hydrolysis is optionally carried out in an acidic medium, for example in the presence of hydrochloric acid, sulfuric acid or methanesulfonic acid. This hydrolysis can also be carried out in an alkaline aqueous-alkaline medium (for example using sodium hydride or potassium hydride).

The nitro derivative of formula VII can be prepared by treatment with a malonic acid derivative of formula VIII

Rzz-CH-COOR '1 (VIII) in which R' 1 and R 'have the meanings given above, to the nitrobenzaldehyde derivative of the general formula IX

(IX) wherein Hal is as defined above.

The reaction is usually carried out in a basic medium (e.g. in the presence of an alkali metal hydrogen carbonate, e.g. sodium hydrogen carbonate, hydride, e.g. sodium hydride or alkoxide, at a temperature between 0 and 150 ° C in an organic solvent such as anhydride , for example acetic anhydride or an amide, for example dimethylformamide, N-methylpyrrolidone, in the presence of a molecular sieve or any other drying agent or also in a solvent mixture such as a mixture of aprotic polar solvent and acetic anhydride, for example dimethylformamide / acid anhydride acetic anhydride or a mixture of N-methylpyrrolidone and acetic anhydride It is also possible to carry out the reaction in a biphasic medium, and it is not necessary to isolate the product of formula VII before carrying out the next reaction.

The fluoronitrobenzaldehyde (IX) is obtained by nitrating the fluorobenzaldehyde (X)

(X in which Hal has the meaning given above.

The reaction is preferably carried out using concentrated nitric acid as a mixture with concentrated sulfuric acid or using a mixture of nitric acid and acetic acid at a temperature between 0 and 90 ° C.

4-Chloro-3-fluorobenzaldehyde can be prepared by the method described in European patent application EP 289 942.

The benzonaphthyridine derivatives of formula I wherein R is cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl, the alkyl moieties of which may optionally form with or via a nitrogen atom to which 5 or A 6-membered heterocyclic group containing optionally another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted on the nitrogen by an alkyl group are new products.

The benzo (b) naphthyridine derivatives of the formula I obtained by the process according to the invention are of particular interest since they lead to a group of particularly effective antibacterial agents defined by the general formula XI

wherein either R '(which represents an alkyl group, a fluoroalkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkoxy group or an alkylamino group) and Het (which represents a nitrogen heterocyclic group) have the meanings defined for the substituents at the 1-position and 8 in European patent application EP 431 991 and in US patent 5,004,745, or R 'is as defined above for formula I and Het means

1-azetidinyl (substituted at the 3-position with R ₂ , which may be a hydrogen atom, a hydroxy group, an amino group, an alkylamino group whose alkyl residue is optionally substituted with an amino group or a hydroxy group, or may be a dialkylamino group whose alkyl group the radicals may optionally form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic group containing optionally another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, or may represent a cycloalkylamino group of 3 to 6 members, or alkanoylamino, N-alkyl-N-alkanoylamino or aminoalkylphenylamino, and substituted in positions 2a and 3 with the substituents R ₃ and R 6 which are the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group having 2 to 4 carbon atoms , phenyl, phenyl substituted, and the like a halogen atom, an alkyl group, an alkyloxy group, a hydroxy group, a nitro group, an amino group, an alkylamino group, a dialkylamino group or a haloalkyl group, or also substituted at the 2-position with R a and R ₄ , which are alkyl groups) alkyl and alkanoyl groups are straight or branched groups having 1 to 4 carbon atoms.

The 1,8-benzo (b) naphthyridine derivatives of formula (XI) are obtained by condensing the heterocycle Het to the henzo (b) naphthyridine of formula (I) using the methods described in European Patent Application EP 431 991 and US Patent 5,004,745 or using are analogous to these methods and optionally converting the ester, amide or nitrile obtained to the acid of formula XI. The efficacy of the benzonaphthyridine derivatives of formula XI has been described in said European patent application and in said US patent. The benzonaphthyridine derivatives of the general Formula XI in which Het is an azetidinyl group also have antibacterial properties. These products have remarkable in vitro potency against gram positive germs as well as against gram negative germs. In vitro, these compounds are active on Staphylococcus aureus IP

8203 at a concentration between 0.06 and 4 pg / cm ³ and on Escherichia coli, strain NIHJ JC2 at a concentration between 0.25 and 20 pg / cm ³ . In vivo, these compounds are effective against experimental infections of mice with Staphylococcus aureus IP 8203 at doses between 10 and 200 mg / kg when administered orally.

The benzo (b) naphthyridine derivatives of formula (I) obtained by the process of the invention may optionally be purified by physical methods such as crystallization or chromatography.

In the case where R is a carboxyl group, the henzo (b) naphthyridine derivatives of the formula I can be converted into metal salts or acid addition salts or nitrogen bases by known methods. These salts can be obtained by treating a product of the invention in a suitable solvent, such as an alcohol, ether or water, or by exchange with an organic acid salt, by treating a product of the invention with a base derived from a metal (e.g. an alkali or alkaline earth metal), an amine or an amine. The salt formed is precipitated after optionally concentrating the solution, then separated by filtration, decantation or lyophilization.

Examples of such salts include alkali metal salts (sodium, potassium, lithium) or alkaline earth metals (magnesium, calcium), ammonium salt, salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine) N, Ν-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine hydrochlorides, and hydrobromic acid addition salts , sulfates, nitrates, phosphates) or organic acids (succinates, fumarates, maleates, methanesulfonates, p-toluenesulfonates, isethionates).

In the following, the invention will be further elucidated by means of examples of specific embodiments thereof, which, however, are illustrative only and in no way limit the scope of the invention, which is clearly defined by the wording of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N-beta-ethoxycarbonylethyl) aminoquinoline

To a solution of 72 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 45.1 N-methyl-N-beta-ethoxycarbonylethylamine in 750 cm ^{3 of} toluene is added 56.2 g of sodium carbonate. The resulting suspension is heated to a temperature of about 90 ° C, then stirred at this temperature for 4 hours. The reaction mixture is then cooled to a temperature of about 400 cm ^{3 of} water. Organic phase under reduced pressure (20 kPa) at a temperature of about 50 ° C. 94 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N-beta-ethoxycarbonylethylamino) quinoline are obtained in the form of an oil which is used as is in the subsequent reaction stages without purification.

° C and then concentrated to dryness three times at

Preparation of 3-ethoxycarbonyl-7,7-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine:. .

To a solution of 26.6 g of sodium ethoxide in 900 cm ^{3 of} absolute ethanol heated to reflux, a solution of 94 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N) is added over 80 minutes. (beta-ethoxycarbonylethyl) aminoquinoline in 300 cm ^{3 of} absolute ethanol. The resulting suspension was stirred for a further 15 minutes while heating to reflux. 38 cm ^{3 of} glacial acetic acid are then poured in over 30 minutes. The reaction mixture is stirred for 15 minutes and then poured over 45 minutes while still refluxing 500 cm ^{3 of} water. The resulting suspension is cooled to about 20 ° C. The precipitate is centrifuged at ° C and washed twice with 300 cm ^{3 of} water. Moisture under reduced pressure (20 kPa) and at a temperature of about 71.5 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo / b of naphthyridine as a yellow solid, m.p. 188 ° C.

Preparation of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine at a temperature of about 20 times is dried at 60 ° C. isolates

To a suspension of 71 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine in 1000 cm ^{3 of} ethanol is added under stirring at about 20 ° C a solution of 3.78 g of potassium iodide in 20 cm ^{3 of} water. The suspension is heated to 77 ° C, then 33 cm @ ^{3 of} 33% by weight hydrogen peroxide are added at this temperature over 60 minutes. The reaction mixture is refluxed for an additional 30 minutes, then cooled to about 20 ° C. At this temperature a solution of about 11.4 g of sodium sulphite in 50 cm ^{3 of} water is poured over 5 minutes. The precipitate obtained is centrifuged at 20 DEG C. and washed twice with 300 cm @ ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa) at a temperature of about 60 ° C. 73 g of 3-ethoxy-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are isolated as a white solid, m.p. > 270 DEG. C. J

2-Chloro-3-ethoxycarbonyl-6,7-difluoroquinoline can be prepared as follows.

50 g of 3-ethoxycarbonyl-6,7-difluorocarbostyril are added to 200 cm @ ^{3 of} phosphoryl chloride over 10 minutes with stirring at 20 DEG. The suspension is heated to about 70 ° C and maintained at this temperature for 3 hours. After cooling to about 10 DEG C., the solution obtained is poured into a mixture of 1000 cm @ ^{3 of} water and 1000 g of crushed ice with stirring. The temperature is allowed to rise to about 20 ° C and the mixture is extracted twice with 500 cm ^{3 of} dichloromethane. The combined organic extracts are washed with 1000 cm ^{3 of} water and 1000 cm ^{3 of} water to which sodium bicarbonate has been added until pH = 7, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 kPa) at a temperature of about 40 kPa. C. 45.6 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline are obtained in the form of a beige solid, m.p. 108 DEG C., which is used without further purification in the next reaction steps.

3-Ethoxy-6,7-difluorocarbostyrene can be obtained as follows.

To a solution of 56.5 g of 3,4-difluoro-6-nitrobenzaldehyde in 92 cm ^{3 of} acetic anhydride, 62.8 g of ethyl malonate and 51 g of sodium hydrogen carbonate are added dropwise with stirring over 10 minutes. The resulting suspension is maintained at about 20 ° C for one hour, then heated to about 75 ° C for 3 hours. At this temperature 400 cm ^{3 of} glacial acetic acid and then 65 cm ^{3 of} water are poured over 30 minutes. The temperature is allowed to stabilize at about 50 ^σ 0, then stirred at this temperature for 30 minutes. 39 g of iron powder are added. This addition is carried out in portions over two hours. The temperature rises to about 85 ° C and the suspension is maintained at this temperature for an additional hour. The precipitated iron salts are centrifuged at about 80 ° C and then washed twice with 150 cm ^{3 of} glacial acetic acid. The filtrate and the acidic washings are combined, then 700 cm ^{3 of} water are added. The precipitate formed is centrifuged at about 20 ° C and washed three times with 500 cm ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 53.5 g of 3-ethoxycarbonyl-6,7-difluorocarbostyril are obtained in the form of a cream solid, m.p. 242 ° C.

3,4-Difluoro-6-nitrobenzaldehyde was prepared as follows.

Ä '

To 520 cm ³ of sulfuric acid cooled to 0 ° C, 60 cm ^{3 of} volatile nitric acid are added with stirring over 30 minutes. 100 g of 3,4-difluorobenzaldehyde are added to the solution obtained at 30 DEG C. over a period of 30 minutes. The temperature is allowed to rise to about 20 ° C and the mixture is stirred at this temperature for three hours. After cooling to about 5 ° C, the reaction mixture is poured into 1200 g of crushed ice over 30 minutes with vigorous stirring. The temperature is allowed to return to about 20 ° C and the mixture is extracted twice with 600 cm ^{3 of} toluene. The organic extracts are combined and washed three times with 1000 cm ^{3 of} water, then concentrated under reduced pressure (20 kPa) and at 50 ° C. 113 g of 3,4-difluoro-6-nitrobenzaldehyde are obtained in the form of a brown oil which is used as such in further syntheses.

Example 2

Preparation of 3-ethoxycarbonyl-6,7-difluoro-2- (N-ethyl-N-3-ethoxycarbonylethyl) aminocholine

To a solution of 10 g of 2-chloro-6,7-difluoroquinoline and 9.7 g of N-ethyl-N-3-ethoxycarbonylethylamine in 120 cm ^{3 of} toluene is added 7.8 g of sodium carbonate. The suspension obtained is about 90 ° C, then at this temperature the mixture is cooled to about 20 100 cm ^{3 of} water. The organic phases are concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 13 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-ethyl-β-ethoxycarbonylethyl) aminoquinoline are obtained in the form of an oil, which is used without further purification in the next reaction steps.

is warmed to room temperature for 4 hours. Reaction C was washed three times

Preparation of 3-ethoxycarbonyl-7,8-difluoro-1-ethyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine

A solution of 68 g of 3-ethoxycarbonyl-6,7-fluoro-2- (N-ethyl-N-) was added over 60 minutes to a solution of 16.1 g of sodium ethoxide in 600 cm ^{3 of} absolute ethanol heated to reflux. β-ethoxycarbonylethyl) aminoquinoline in 200 cm ^{3 of} absolute ethanol. The resulting suspension, which was still heated to reflux, was stirred for a further 60 minutes. 20 cm @ ^{3 of} glacial acetic acid are then poured in over 30 minutes. The reaction mixture is stirred for a further 15 minutes and then poured under reflux with 400 cm @ ^{3 of} water. The resulting suspension is cooled to about 20 ° C. The precipitate formed is drained at approximately 20 DEG C. and washed twice with 200 cm @ ^{3 of} water. The wet product is dried under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 52.4 g of 3-ethoxycarbonyl-7,8-difluoro-letyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine are isolated in the form of a solid golden yellow product, m.p. 152 C.

Preparation of 3-ethoxycarbonyl-7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine

To a suspension of 33 g of 3-ethoxycarbonyl-7,8-difluoro-1-ethyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine in 1000 cm ^{3 of} ethanol is stirred and at a temperature of about 20 ° C a solution of 1.7 g of potassium iodide in 10 cm ^{3 of} water is added. The suspension is heated to 77 ° C and then 12.7 cm ^{3 of} hydrogen peroxide (33% by weight) are added at this temperature over 30 minutes. The reaction mixture is refluxed for a further 30 minutes, then cooled to about 20 ° C. At this temperature, a solution of 6 g of sodium sulphite in 20 cm ^{3 of} water is poured over 5 minutes while pouring. The precipitate formed is drained at approximately 20 DEG C. and washed twice with 150 cm @ ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 28.7 g of 3-ethoxy-7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are isolated in the form of a pale yellow product, m.p. 270 ° C.

Example 3

Preparation of 3-ethoxycarbonyl-6,7-difluoro-2- (N-cyclopropyl-N-β-ethoxycarbonylethyl) aminocholine

To a solution of 3.48 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-cyclopropyl-Nβ-ethoxycarbonylethylamine in 10 cm ^{3 of} toluene is added 3 g of sodium carbonate. The resulting suspension is heated to reflux and then stirred at this temperature for 15 hours. The reaction mixture is then cooled to about 20 DEG C., 30 cm @ ^{3 of} water and 4.5 cm @ ³ of acetic acid are added thereto. After decantation, the reaction mixture is washed twice with 10 cm @ ^{3 of} water. The organic is concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 3.3 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-cyclopropyl-Nβ-ethoxycarbonylethyl) aminoquinoline are obtained in the crude state as an oil which is used without further purification in the next reaction steps.

Preparation of 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine

A solution of 3-ethoxycarbonyl-6,7-difluoro-2- (N-cyclopropyl-N-β-ethoxycarbonylethyl) is added to a solution of 1.6 g of sodium ethoxide in 40 cm ^{3 of} absolute ethanol at reflux. of aminoquinoline in 20 cm ^{3 of} absolute ethanol. The resulting solution was stirred for an additional 60 minutes while heating to reflux. 2.6 cm ^{3 of} glacial acetic acid are then poured in over 10 minutes. The reaction mixture is then stirred for a further 15 minutes. then it is poured over 5 minutes while heating to reflux with 26 cm ^{3 of} water. The resulting suspension is cooled to about 20 ° C. The precipitate formed is drained at a temperature of about 20 DEG C. and washed twice with 10 cm @ ^{3 of} water. The wet product is dried under reduced pressure (20 kPa) and at a temperature of about 60 ° C. 1.25 g of crude 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine are isolated as a yellow solid. mp 172 ° C.

Preparation of 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine

To a suspension of 1 g of 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine in 14 cm ^{3 of} ethanol was stirred and at 20 ° C a solution of 0.053 g of potassium iodide in 0.5 cm ^{3 of} water is added. The suspension obtained is heated to 77 DEG C. and 0.5 cm @ ^{3 of} 33% by weight hydrogen peroxide are introduced at this temperature over 5 minutes. The reaction mixture is refluxed for an additional 60 minutes, then cooled to about 20 ° C. At this temperature, 1.06 cm @ ^{3 of} 1N sodium sulphite solution is poured over 5 minutes. The precipitate formed is drained at a temperature of about 20 DEG C. and washed twice with 10 cm @ ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa and at a temperature of about 60 DEG C.). 0.7 g of 3-ethoxycarbonyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1 is isolated. 8-benzo (b) naphthyridine, crude, in the form of a solid beocook product, m.p. 210 ° C.

Example 4

Preparation of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N-β-cyanoethylamino) quinoline. To a solution of 16.3 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 10 g of N-methyl-Nβ-cyanoethylamine in 160 cm ^{3 of} toluene is added 19.08 g of sodium carbonate. The resulting suspension is heated to reflux and then stirred at this temperature for 4 hours. The reaction mixture is then cooled to about 20 DEG C. and then washed three times with 50 cm @ ^{3 of} water. The organic phase is concentrated under reduced pressure and at a temperature of about 50 ° C. 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-Nβ-cyanoethylamino) quinoline are obtained in the form of an oil which is used without further purification in the next reaction steps.

3-Cyano-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine was prepared as follows.

A solution of 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N) was added to a solution of 8.74 g of potassium tert-butoxide in 200 cm @ ^{3 of} tetrahydrofuran cooled to -10 DEG C. over 60 minutes. of β-cyanoethylamino) quinoline in 50 cm ^{3 of} tetrahydrofuran. The resulting suspension was then stirred at -10 ° C for a further 30 minutes. 4 cm @ ^{3 of} glacial acetic acid are then added. The tetrahydrofuran is evaporated under reduced pressure (20 kPa). The crude reaction mixture is taken up in 200 cm @ ^{3 of an} aqueous-alcohol mixture of ethanol and water (70:30 by volume). The precipitate formed is filtered off, washed twice with 50 cm @ ^{3 of} water and then dried under reduced pressure (20 kPa). 16.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine are isolated as a solid gold-yellow product at a temperature of mp 144 ° C.

3-Cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared as follows.

To a suspension of 8.6 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine in 350 cm @ ^{3 of} ethanol at A solution of 0.47 g of potassium iodide in 5 cm @ ^{3 of} water is added at about 20 DEG C. with stirring. The suspension is heated to 77 ° C and then 33% hydrogen peroxide (1 ml) is added over 10 minutes at this temperature. The reaction mixture is then maintained at reflux for an additional 30 minutes, then cooled to about 20 ° C. At this temperature, 10 cm ^{3 of} sodium sulphite (1N) are added over 5 minutes. The precipitate formed is drained at approximately 20 DEG C. and washed twice with 20 cm @ ^{3 of} water. The wet product is dried under reduced pressure (20 kPa) at about 50 ° C. 8 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are isolated in the form of a pale yellow product, m.p. 380 ° C.

Example 5

3-Ethoxy-6,7-difluoro-2- (N-methyl-N-B- (N ', N'-dimethylaminocarbonylethyl) amino) quinoline was prepared as follows.

To a solution of 26 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 25 g of N-methyl-N-β- (N ', N'-dimethylaminocarbonylethyl) amine in 300 cm ^{3 of} toluene is added 31 g of sodium carbonate. The suspension is then heated to reflux and stirred at this temperature for 2 hours 30 minutes. The reaction mixture is then cooled to a temperature in the region of 20 DEG C. and then washed three times with 100 cm @ ^{3 of} water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 35 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N-β- (N ', N'-dimethylaminocarbonylethyl) amino) quinoline are obtained in the form of an oil which is used without further purification in further reaction stages.

N, N-Dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8benzo [b] naphthyridine-3-carboxamide was prepared as follows.

A solution of 35 g of 3-ethoxycarbonyl-6,7-difluoro-2-N-methyl-N is added to a solution of 15.7 g of potassium tert-butoxide in 150 cm @ ^{3 of} tetrahydrofuran cooled to 0 DEG C. over 75 minutes. -β- (N ', N'-dimethylaminocarbonylethyl) aminoquinoline in 150 cm ^{3 of} tetrahydrofuran. The suspension obtained is then stirred at 0 DEG C. for a further 30 minutes, then 8 cm @ ^{3 of} glacial acetic acid are added. The tetrahydrofuran is evaporated off under reduced pressure (20 kPa). The crude reaction mixture is taken up in 200 cm @ ^{3 of} an ethanol / water mixture (70:30 by volume). The precipitate formed is filtered off, washed three times with 100 cm @ ^{3 of} water and then dried under vacuum (20 kPa). 25 g of N, N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine-3-carboxamide is isolated as a solid. lemon-yellow product, m.p. 206 ° C.

N, N-Dimethyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared as follows.

To a suspension of 25 g of N, N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine-3-carboxamide in 1000 cm ^{3 of} ethanol A solution of 1.35 g of potassium iodide in 10 cm @ ^{3 of} water is stirred at about 20 DEG C. with stirring. The suspension is heated to 77 ° C and 33% hydrogen peroxide is added at this temperature over 20 minutes. The reaction mixture was then heated to reflux for one hour and 30 minutes, then cooled to about 20 ° C. At this temperature, 30 cm @ ^{3 of a} 1N sodium thiosulphate solution are poured over 5 minutes. The precipitate formed is drained at approximately 20 DEG C. and washed twice with 60 cm @ ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 19.5 g of N, N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxamide are isolated as a pale yellow product. mp 324 ° C.

Example 6

3-Ethoxy-6,7-difluoro-2- (N-methyl-N-β-aminocarbonylethylamino) quinoline was prepared as follows.

To a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-Nβ-aminocarbonylethylamine in 40 cm ^{3 of} toluene is added 4.4 g of sodium carbonate. The suspension obtained is then heated to reflux and then stirred at this temperature for 2 hours 30 minutes. The reaction mixture is then cooled to about 20 DEG C. and then washed with ³ times 25 cm @ ^{3 of} water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at 50 ° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-N-β-aminocarbonylethylamino) quinoline are obtained in the form of an oil which is used as is in the following stages.

3-Carboxamide-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8benzo [b] naphthyridine was prepared as follows.

A solution of 4.23 g of 3-ethoxycarbonyl-6,7-difluoro-2- (N-methyl-) is added to a solution of 1.8 g of potassium tert-butoxide in 50 cm @ ^{3 of} tetrahydrofuran cooled to 0 DEG C. over 30 minutes. N-β-aminocarbonylethylamino) quinoline in 20 cm ^{3 of} tetrahydrofuran. The suspension obtained is then stirred at 0 DEG C. for a further 30 minutes and then 2 cm @ ^{3 of} glacial acetic acid are added. The tetrahydrofuran is evaporated off under reduced pressure (20 kPa). The crude reaction product is taken up in 10 cm @ ^{3 of an} aqueous-alcohol mixture of ethanol and water (70:30 by volume). The precipitate formed is filtered off, washed 3 times with 10 cm @ 3 ^: dried under reduced pressure (20 kPa). Boxamide-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine is isolated as a yellow solid, m.p. 182 DEG. C.

water and then 1.6 g of 3-car3-carboxamide-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo. (b) Naphthyridine was prepared as follows.

To a suspension of 1.3 g of 3-carboxamide-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine in 25 cm @ ^{3 of} ethanol at A solution of 0.1 g of potassium iodide in 1 cm ^{3 of} water is added at about 20 ° C. The suspension is then heated to 77 ° C and then 1.5 cm ^{3 of} 33% by weight hydrogen peroxide are added at this temperature over 5 minutes. The reaction mixture was refluxed for an additional 1 hour at a temperature of about 20 ° C. While maintaining the boiling point below 30 minutes, then cooled to the temperature is added 1 cm ³ IN sodium sulfite solution. The precipitate formed is drained at a temperature in the region of 20 DEG C. and then washed twice with 5 cm @ ^{3 of} water. The wet product obtained is dried under reduced pressure (20 kPa) and at a temperature of about 50 ° C. 1.1 g of 3-carboxamido-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are isolated as a solid orange product, m.p. 318 DEG. C.

Example 7

The following products were prepared as described in Example 5:

N, N-dimethyl-7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,5-benzo [b] phthyridine-3-carboxamide,

N, N-dimethyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxamide,

N, N-diethyl-7, S-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxamide,

N, N-diethyl-7,8-difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxamide,

N, N-diethyl-7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8benzo [b] naphthyridine-3-carboxamide,

1- (7,8-Difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) pyrrolidine, 1- (7,8-difluoro- l-ethyl-4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-carbonyl) pyrrolidine

1- (7,8-Difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) pyrrolidine, 1- (7 _/ 8- difluoro-l-methyl-4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-karbony1) piperidine

1- (7,8-Difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzonaphthyridine-3-carbonyl) piperidine,

1- (7,8-Difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) piperidine,

1- (7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) morpholine, 1- (7,8-difluoro-1) ethyl-4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-carbonyl) morpholine,

1- (7,8-Difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) morpholine,

1- (7,8-dif1uór-1-mety1-4-oxo-1,4-dihydro-l, 8-benzo / b / naphthyridine-3-carbonyl) morpholine,

1- (7,8-dif1uór-1-ethyl-4-oxo-1,4-dihydro-l, 8-benzo / b / naphthyridine-3-karbony1) thiomorpholine,

1- (7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) thiomorpholine, 1- (7,8-difluoro-1) methyl-4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-karhonyl) -4-methylpiperazine,

1- (7,8-Difluoro-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carbonyl) -4-methylpiperazine and

l- (7,8-difluoro-l-cyclopropyl-4-oxo-l, 4-dihydro-l, 8-benzo / b / naphthyridine-3-carbonyl) -4-methylpiperazine. " The products of formula I obtained in the preceding examples can be used as follows.

Application Example 1

3-Fluoro-7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was prepared as follows.

A suspension of 2.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine in 100 cm ^{3 of} dimethyl sulfoxide is heated to 80 ° C in the presence of 2 cm ^{3 of} N-methylpiperazine. The reaction mixture is maintained at this temperature for 8 hours. The resulting solution was cooled to room temperature and stirred at this temperature for 15 hours. The precipitate formed is filtered off, washed three times with 20 cm @ ^{3 of} water and dried under vacuum (20 kPa) at 50 DEG. 2.6 g of 3-cyano-7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,8-benzo [b] naphthyridine are obtained in the form of a yellow precipitate, m.p. 335 ° C.

7-Fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared as follows.

A suspension of 2 g of 3-cyano-7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine was added to the suspension. Heat 40 cm @ ^{3 of} 12N hydrochloric acid to reflux. The reaction mixture is maintained at this temperature for 15 hours. The resulting solution was cooled to room temperature. The crystallized product is filtered off, washed with water until neutral and dried under reduced pressure (20 kPa) at 50 ° C. 1.5 g of 7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid are obtained. in the form of the monohydrochloride. The product obtained is in the form of yellow crystals, m.p. 290 DEG C. (decomposition).

Application Example 2

A suspension of 2.96 g of 7,8-difluoro-N, N-dimethyl-4-oxo-1-methyl-1,4-dihydro-1,8-benzo [b] naphthyridine, 1.12 g of 1-methylpiperazine and 1, 55 g of potassium carbonate in 100 cm @ ^{3 of} dimethyl sulfoxide are heated to about 80 DEG C. for 5 hours with stirring. After cooling to about 20 DEG C., 100 cm @ ^{3 of} water are added to the reaction mixture. The insoluble matter is centrifuged, washed twice with 30 cm ^{3 of} water and twice with 30 cm ^{3 of} ethanol.

2.3 g of N, N-dimethyl-7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine are obtained. -3-carboxamide in the form of a yellow solid which decomposes at 275 ^{, =>} C.

A solution of 0.5 g of N, N-dimethyl-7-fluoro-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine- The 3-carboxamide in 10 cm ^{3 of} 6N hydrochloric acid is heated with stirring at about 95 ^and C for 5 hours. After cooling to about 20 ° C, the undissolved solid is centrifuged, washed three times with 20 cm ^{3 of} water and twice with 10 cm ^{3 of} ethanol.

The product obtained is suspended in 30 cm @ ^{3 of} water. 0.6 cm @ ^{3 of} an aqueous potassium hydroxide solution is added and the mixture is stirred for one hour at a temperature of about 20 DEG. The insoluble matter is centrifuged and washed twice with 20 cm @ ^{3 of} water and twice with 10 cm @ ^{3 of} ethanol. After recrystallization from 15 cm @ ^{3 of} dimethylformamide, 0.15 g of 7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) is obtained. 4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridene-3-carboxylic acid is a yellow solid which decomposes at 354 ° C.

Application Example 3

A suspension of 1.3 g of 7,3-difluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxamide, 0.54 g of 1-methylpiperazine and 0, 75 g of potassium carbonate in 25 cm < ^{3 > of} dimethylsulfoxide are heated at about 80 [deg.] C. for 6 hours. After cooling to about 20 DEG C., 100 cm @ ^{3 of} water are added to the reaction mixture. The insoluble matter is centrifuged, washed twice with 20 cm ^{3 of} water and twice with 20 cm ^{3 of} ethanol.

The product obtained is chromatographed on 20 g of silica gel

2Ί (0.063-0.200 mm) in suspension in a mixture of dichloromethane with a 10% methanol content. The reaction impurities are separated by elution with 500 cm ^{3 of} said solvent mixture. The desired product is then eluted with 500 cm ^{3 of the} same solvent mixture. After concentration to dryness under reduced pressure (20 kPa) and at a temperature of about 40 ° C, the solid residue is recrystallized from 25 cm ³ of dimethylformamide, centrifuged and washed twice with 30 cm ^{3 of} about 70 ° C of warm ethanol.

0.6 g of 7-fluoro-1-methyl-8- (4-methyl-1-piperazinyl) -4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridio-3 is obtained. -carboxamide in the form of a yellow solid which decomposes at 265 ^° C.

7-Fluoro-8- (4-methyl-1-piperazine) -1-methyl-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine-3-carboxylic acid was prepared under conditions of Example 2, but starting from 0.3 g of 7-fluoro-1-methyl-8- (4-methyl-1-piperazine) -1-oxo-1,4-dihydro-1,8-benzo / b / naphthyridine-3-carboxamide. After cooling to about 20 DEG C., 50 cm @ ^{3 of} water are added to the reaction mixture. The insoluble matter is centrifuged and washed twice with 10 cm @ ^{3 of} water.

The product obtained is suspended in 20 cm @ ^{3 of} water, then 0.4 cm @ ^{3 of} an aqueous potassium hydroxide solution are added to the suspension obtained, and the mixture is stirred at a temperature in the region of 20 DEG C. for one hour. The insoluble matter is centrifuged, washed three times with 10 cm @ ^{3 of} water, washed twice with 10 cm @ ^{3 of} ethanol and recrystallized in 20 cm @ ^{3 of} dimethylformamide. 0.17 g of .7-fluoro-1-methyl-N-methyl-1-piperazin-4-oxo-1,4-dihydro-1,8-benzo [b] naphthyridine is obtained. -3-carboxylic acid as a yellow solid which decomposes at 354 ° C.

Claims (3)

PATENT CLAIMS A novel process for the preparation of benzo (b) naphthyridines of the general formula wherein R represents a carboxyl group, an alkoxycarbonyl group, a cyano group, a carbamoyl group, an alkylcarbamoyl group, a benzylcarbamoyl group, a hydroxyethylcarbamoyl group, a dialkylaminoethylcarbamoyl group or with a nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic group optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted on the nitrogen by an alkyl group, R 'is hydrogen or an alkyl group, a fluoroalkyl group, a carboxyalkyl group, a C3-6 cycloalkyl group, a fluorophenyl group, a difluorophenyl group, an alkyloxy group or an alkylamino group, and Hal represents a halogen atom, and salts thereof, if any, e will be held the following operations: 1) condensation of an amine of the formula R '-NH-CH 2 -CH 2 -R wherein R' is as defined above and R is an alkyloxycarbonyl, cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl moiety wherein optionally form, with the nitrogen atom to which they are attached, a 5- or 2-carbon atom A 6-membered heterocyclic group, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted on the nitrogen atom with an alkyl group, with a chlorofluoroquinoline of the formula wherein Hal is as defined above or an alkyl group having the direct or a branched carbon carbon, and R 1 represents the hydrogen atom of said alkyl group having 1 to 4 atoms 2) cyclization of the thus obtained fluoroquinoline of the formula wherein R ', R and Hal have the above meanings and R _x has the meaning given in 1), and 3) oxidation of 1,2,3,4-tetrahydro-1,8-benzo [b] naphthyridine of the general formula in which Hal, R 'and R have the meanings given above, then obtaining an ester in which R represents an alkyl group, optionally is converted to an acid in which R is a hydrogen atom and the resulting acid is optionally converted to a salt. A benzonaphthyridine derivative of the general formula wherein R 'and Hal have the meanings given in claim 1 and R represents cyano, carbamoyl, alkylcarbamoyl, benzylcarbamoyl, hydroxyethylcarbamoyl, dialkylaminoethylcarbamoyl or dialkylcarbamoyl, the alkyl moieties of which may optionally form alkyl moieties. the nitrogen atom to which they are attached a 5- or 6-membered heterocycle 31 Optionally containing an oxygen atom, an atom optionally substituted on the nitrogen atom with a heteroatom selected from sulfur and a nitrogen atom with an alkyl group.